Anti-angiogenesis therapy based on the bone marrow-derived stromal cells genetically engineered to express sFlt-1 in mouse tumor model.
BACKGROUND
Bone marrow-derived stromal cells (BMSCs) are important for development, tissue cell replenishment, and wound healing in physiological and pathological conditions. BMSCs were found to preferably reach sites undergoing the process of cell proliferation, such as wound and tumor, suggesting that BMSCs may be used as a vehicle for gene therapy of tumor.


METHODS
Mouse BMSCs were loaded with recombinant adenoviruses which express soluble Vascular Endothelial Growth Factor Receptor-1 (sFlt-1). The anti-angiogenesis of sFlt-1 in BMSCs was determined using endothelial cells proliferation inhibition assay and alginate encapsulation assay. The anti-tumor effects of BMSCs expressing sFlt-1 through tail-vein infusion were evaluated in two mouse tumor metastases models.


RESULTS
BMSCs genetically modified with Adv-GFP-sFlt-1 could effectively express and secret sFlt-1. BMSCs loaded with sFlt-1 gene could preferentially home to tumor loci and decrease lung metastases and prolong lifespan in mouse tumor model through inducing anti-angiogenesis and apoptosis in tumors.


CONCLUSIONS
We demonstrated that BMSCs might be employed as a promising vehicle for tumor gene therapy which can effectively not only improve the concentration of anticancer therapeutics in tumors, but also modify the tumor microenvironment.
Hu
M
M
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, PR China. jlygym_w@163.com
Yang
J-L
JL
Teng
H
H
Jia
Y-Q
YQ
Wang
R
R
Zhang
X-W
XW
Wu
Y
Y
Luo
Y
Y
Chen
X-C
XC
Zhang
R
R
Tian
L
L
Zhao
X
X
Wei
Y-Q
YQ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000628:therapy*; D017154:Stromal Cells / Q000378:metabolism*; D014162:Transfection; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism
C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1